1. Field of the Invention
The present invention relates to a new compound for treating central nervous disorders and more particularly the invention refers to a compound comprising valproic acid or any derivative thereof covalently bound to myo-inositol, wherein the therapeutic activity of compound combining valproic acid and myo-inositol is increased several times as compared to the specific therapeutic activity of the valproic acid alone.
2. Description of the Prior Art
Central nervous disorders comprise several affections like epilepsy, bipolar disorders and migraine, and affect an import part of a population particularly insofar as to migraine and bipolar disorders is concerned. Bipolar disorders are those related to affective disorders and more particularly to changes in mood and disturbances concerning depression and mania. While mania involves excessive exuberance and enthusiasm, depression, on the opposite, involves apathy and low self-esteem, among other symptoms. There are individuals that are affected by both depression and mania and this disorder is known as bipolar disorder. Unipolar disorder is that one involving only one of both affections mentioned before.
While anti-depressants are effective for treating unipolar depression these drugs are not effective for mania. Valproic acid a relatively new anti-epileptic drug has demonstrated to be effective in treatment of mania in bipolar depression. However, valproic acid has different drawbacks and disadvantages, one of them is the short half life time, therefore, a dose must be administered to a patient several times a day to prevent the drug fluctuations of plasma concentrations. In addition, therapeutic doses of valproic acid and several of its derivatives are toxic and provide side effects, such as nausea, dizziness, etc. in many patients.
As disclosed in U.S. Pat. No. 4,595,695, a prodrug of valproic acid comprising 2-propylpentanoil-di-n-propyl acetate has been developed to prevent the above disadvantages however this ester prodrug has proved to be toxic to animals and as anti-epileptic and psychotic drug has not been effective. In addition, this prodrug has low bioavailability and slow absorption.
On the other hand, myo-inositol is known in the nutritional field to be an important nutritional component of the diet. U.S. Pat. No. 5,763,392 to Hansen et al. discloses the use of myo-inositol as an effective plasma glucose lowering agent. Myo-inositol is the major nutritionally active form of inositol, is vital to many biological processes of the body, participating in a diverse range of activities. Myo-inositol is one of nine distinct isomers of inositol. It is essential for the growth of rodents, but not for most animals, including humans. Humans can make myo-inositol endogenously, which they do from glucose, and, even though myo-inositol is sometimes referred to as a vitamin, it is not a vitamin for humans or most animals. However, the dietary intake of myo-inositol can influence the levels of circulating and bound myo-inositol in the body and may influence certain biological activities. Nutritional supplementation of this cyclitol may affect behavior and may have anti-depressant and anti-anxiety activities.
Myo-inositol is also known as inositol, hexahydroxycyclohexane, cyclohexanehexol, and, chemically, as cis-1,2,3,5-trans-4,6-cyclohexanehexol The mechanism of action of myo-inositol has yet to be fully elucidated. However, much is known about the biological roles of myo-inositol and some speculation can be made. Myo-inositol is metabolized to phosphatidylinositol, which makes up a small, but very significant, component of cell membranes.
Phosphatidylinositol can be converted to phosphatidylinositol-4,5-bisphosphate, a key intermediate in biological signaling. Phosphatidylinositol-4,5-bisphosphate is the precursor of at least three second-messenger molecules. These are inositol-1,4,5-triphosphate, which modifies intracellular calcium levels, diacylglycerol, which regulates some members of the protein kinase C family, and phosphatidylinositol-3,4,5-triphosphate, which is involved in signal transduction.
Some of the second-messenger activity is related to activation of serotonin receptors. It is hypothesized that the mechanism of action of myo-inositol's possible benefit in the management of depression, panic attacks and obsessive-compulsive behavior may be explained by myo-inositol's role as a second-messenger precursor.
Myo-inositol is absorbed from the small intestine following ingestion and is transported by the portal circulation to the liver and then by the systemic circulation to various tissues in the body, including the brain. Myo-inositol crosses the blood-brain barrier.
Within the liver and the various tissues of the body, myo-inositol enters into a wide range of diverse biochemical pathways. Myo-inositol reacts with CDP-diacylglycerol to form the phospholipid phosphatidylinositol, which can be incorporated into membrane structure. Phosphatidylinositol, via kinase reactions, forms phosphatidyl-4,5-bisphosphate, which is the precursor to inositol-1,4,5-triphosphate, diacylglycerol, phosphatidylinositol-3,4,5-triphosphate, myo-inositol 1,3,4-triphosphate and myo-inositol 1,3,4,5-tetrakis-phosphate, among others. The myo-inositol phosphates can be dephosphorylated via phosphatases.
Considering the several drawbacks of the valproic acid some modified drugs have been made with the aim of overcoming the undesirable side effects and the disadvantageous physical and pharmacokinetic of the drug, however those drug modifications, while improved the drugs characteristics, have a less potent therapeutic effect.
In an attempt to prolong the effect of valproic acid the concept of prodrug which will be biotransformed almost completely to valproic acid in a rate limiting fashion has been tried, so far without success. This drug is 2-propylpentanol-di-n-propyl acetate. However this ester has proved to be very toxic to animals and was not introduced for therapy.
The novel compounds according to the present invention are myo-inositol ester prodrugs of an acid. Other such esters, serving as prodrugs are already in therapeutic use. For example 1′-ethoxycarbonyloxyethyl ester prodrugs of the penicillin series such as, for example, .alpha.-aminopenicillins and penicillin G are known.
It has also been found that the absorption of such esters from the intestinal tract is superior to the absorption of the corresponding free acids, which means that upon oral administration they yield higher blood concentrations than the corresponding free acid of .alpha.-aminopenicillin.
Usually the unionized form of a drug is absorbed more efficiently than its ionic species. In the case of valproic acid, the carboxylic group is significantly ionized at physiological pH. The result is that valproic acid is poorly absorbed through lipid-water membrane barriers, and in addition to the prodrugs and esters of valproic acid is very important to find ways to reduce the bounds to plasmatic proteins.
In view of the foregoing it would be very desirable to find a new compound based on valproic acid that, in combination with the benefits of myo-inositol, is effective in the treatment of central nervous disorders, such as bipolar disorders, and with reduced doses of the associated drugs in order to reduce side effects and toxicity.